title: The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.
abstract: Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.
authors.affiliation: Genetic Medicine Central California, Fresno, CA 93701, USA. ccurry@fresno.ucsf.edu
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Erica
authors.initials: E
authors.lastname: Grant
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
authors.forename: Carol
authors.initials: C
authors.lastname: Anderson
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Aylsworth
authors.forename: Taha Ben
authors.initials: TB
authors.lastname: Saad
authors.forename: Victor V
authors.initials: VV
authors.lastname: Chizhikov
authors.forename: Giedre
authors.initials: G
authors.lastname: Dybose
authors.forename: Christina
authors.initials: C
authors.lastname: Fagerberg
authors.forename: Michelle
authors.initials: M
authors.lastname: Falco
authors.forename: Christina
authors.initials: C
authors.lastname: Fels
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.forename: Jesper
authors.initials: J
authors.lastname: Graakjaer
authors.forename: Donatella
authors.initials: D
authors.lastname: Greco
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hair
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hopkins
authors.forename: Marlene
authors.initials: M
authors.lastname: Huggins
authors.forename: Roger
authors.initials: R
authors.lastname: Ladda
authors.forename: Chumei
authors.initials: C
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Moeschler
authors.forename: Malgorzata J M
authors.initials: MJ
authors.lastname: Nowaczyk
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Ozmore
authors.forename: Santina
authors.initials: S
authors.lastname: Reitano
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Laura
authors.initials: L
authors.lastname: Roos
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Schnur
authors.forename: Susan
authors.initials: S
authors.lastname: Sell
authors.forename: Pim
authors.initials: P
authors.lastname: Suwannarat
authors.forename: Dea
authors.initials: D
authors.lastname: Svaneby
authors.forename: Marta
authors.initials: M
authors.lastname: Szybowska
authors.forename: Mark
authors.initials: M
authors.lastname: Tarnopolsky
authors.forename: Raymond
authors.initials: R
authors.lastname: Tervo
authors.forename: Anne Chun-Hui
authors.initials: AC
authors.lastname: Tsai
authors.forename: Megan
authors.initials: M
authors.lastname: Tucker
authors.forename: Stephanie
authors.initials: S
authors.lastname: Vallee
authors.forename: Ferrin C
authors.initials: FC
authors.lastname: Wheeler
authors.forename: Dina J
authors.initials: DJ
authors.lastname: Zand
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: Swaroop
authors.initials: S
authors.lastname: Aradhya
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics*; D048948:14-3-3 Proteins / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002648:Child; D002653:Child Behavior Disorders / Q000235:genetics / Q000473:pathology*; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000473:pathology*; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D006801:Humans; D007223:Infant; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010641:Phenotype
chemical_list: D048948:14-3-3 Proteins; D008869:Microtubule-Associated Proteins; C482983:YWHAE protein, human; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human
keywords: 17p13.3; ABR; BHLHA9; LIS1; YWHAE; autism; cleft lip/palate; marfanoid habitus; microarray; split hand foot long bone deficiency